Genetic instability plays a prominent role in biology and medicine. It is associated with diverse biological processes such as aging, developmental defects and tumorigenesis. At the same time, induction of genetic instability with ionizing radiation is used to treat cancer. Here, we report that genetic instability also has a profound effect on protein quality control. HSP90 is a chaperone that folds a subset of the proteome called clients, which are composed of proteins important for signaling, such as kinases, steroid receptors, transcription factors and enzymes. Therefore, the impact of HSP90 activity extends far beyond the chaperoning of its clients. HSP90 has been called the cancer chaperone because its activity promotes cancer cell growth, survival and invasion. In vertebrates, the two HSP90 isoforms have different expression patterns and functions: HSP90&#946; is constitutively expressed and is essential for viability, whereas the expression of HSP90&#945; is induced by stress and tumorigenesis and is not essential for viability. It is not known how the two isoforms are differentially regulated. DNA-activated protein kinase, a double-strand DNA-break sensor, phosphorylates Thr 5 and 7 of HSP90&#945; in response to DSBs in vivo. Phosphorylation of Thr 5 and 7 are important for DSB-induced phosphorylation events. Moreover, the extent of apoptosis is regulated by the HSP90&#945; phosphorylation. Thus, DNA-PK mediates an unexpected coordination between protein quality control and genetic integrity, providing insights into how genetic instability can have global cellular effects.